The role of intrinsic enteric nerves in the control of small intestinal motility is incompletely understood. A major limitation has been the inability to induce selective permanent defunctioning of these nerves. The aims of this project are 1) to induce selective degeneration of the intrinsic nerves of the small intestine by local intra-arterial perfusion of a neurotoxin (cobalt chloride); 2) to study the effects of intrinsic denervation on the myoelectric and motor activity in the fasted and fed states; and 3) to study the effect of denervation on the propulsion of intraluminal contents. Studies will be performed on conscious dogs chronically implanted with seromuscular electrodes and strain gauges. The t-tube cannulae will be inserted into mesenteric arteries for the local administration of drugs. Denervation will be achieved by the perfusion of a 20 cm segment of small bowel with a solution of cobalt chloride. The extent of denervation will be assessed by light and electron microscopy as well as by immunohistochemical studies. In vitro studies of the contractility of the cobalt-treated intestinal segments will also be performed. The initial objectives will be to study the effects of denervation on the basic patterns of intestinal motility. The spontaneous activity of the denervated segment will be studied at rest, during feeding, and in response to local and intravenous administration of pharmacologic stimulants. The role of intrinsic nerves in coordinated intestinal motility will be investigated by studying the effects of denervation on the propagation of both spontaneous and pharmacologically induced migrating motor complexes (MMC's). Subsequently, the role of intrinsic nerves in the initiation of intestinal reflexes will be investigated by studying the effect of denervation on reflex-inhibition of MMC propagation induced by local cholinergic stimulation. The final series of experiments will investigate the effect of denervation on the propulsion of intraluminal contents. Dogs will be prepared with an intraluminal perfusion catheter and a fistula in addition to the electrodes and strain gauges. Intestinal transit time will be measured using intestinal perfusion techniques and a radionucleide-labelled liquid bolus. Intestinal transit will be measured during phases II and III of the MMC as well as after feeding. The studies outlined in the project will enable examination of the role of intrinsic nerves in small intestinal motility while maintaining muscular integrity. They will, therefore, allow a more complete comprehension of the control of small intestinal motility. Such information is essential to our understanding of small intestinal physiology as well as the mechanisms underlying motor disorders such as intestinal pseudo-obstruction.